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Abstract Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.

CD8+ T cells play basic roles in the immune system in a tumor microenvironment (TME) to fight cancer. Several reports have suggested signs of the involvement of tumor protein p53 (TP53) in a complex immune system network. Moreover, our previous research indicated that TP53 orchestrates the polarization and infiltration of macrophages into the TME. In the present study, the clinical function of TP53 status (wild/mutant) in CD8+ T cell infiltration was assessed using more than 10,000 The Cancer Genome Atlas (TCGA) samples from 30 cancer types through Tumor Immune Estimation (TIMER). Our investigation revealed that CD8+ T cell infiltration was higher in head and neck squamous cell carcinoma (HNSC) and uterine corpus endometrial carcinoma (UCEC) patients with wild-type TP53 than in those with mutant TP53. Wild-type TP53 conferred a good prognosis for HNSC and UCEC (P

The SARS-CoV-2 infection activates host kinases and causes high phosphorylation in both the host and the virus. There were around 70 phosphorylation sites found in SARS-CoV-2 viral proteins. Besides, almost 15,000 host phosphorylation sites were found in SARS-CoV-2-infected cells. COVID-19 is thought to enter cells via the well-known receptor Angiotensin-Converting Enzyme 2 (ACE2) and the serine protease TMPRSS2. Substantially, the COVID-19 infection doesn’t induce phosphorylation of the ACE2 receptor at Serin-680(s680). Metformin's numerous pleiotropic properties and extensive use in medicine including COVID-19, have inspired experts to call it the “aspirin of the twenty-first century”. Metformin's impact on COVID-19 has been verified in clinical investigations via ACE2 receptor phosphorylation at s680. In the infection of COVID-19, sodium-dependent transporters including the major neutral amino acid (B0AT1) is regulated by ACE2. The structure of B0AT1 complexing with the COVID-19 receptor ACE2 enabled significant progress in the creation of mRNA vaccines. We aimed to study the impact of the interaction of the phosphorylation form of ACE2-s680 with wild-type (WT) and different mutations of SARS-CoV-2 infection such as delta, omicron, and gamma (γ) on their entrance of host cells as well as the regulation of B0AT1by the SARS-CoV-2 receptor ACE2. Interestingly, compared to WT SARS-CoV-2, ACE2 receptor phosphorylation at s680 produces conformational alterations in all types of SARS-CoV-2. Furthermore, our results showed for the first time that this phosphorylation significantly influences ACE2 sites K625, K676, and R678, which are key mediators for ACE2-B0AT1 complex.

Researchers had difficulty studying pure full-length pMMO due to the solubility problem and loss of enzymatic activity after its elimination from the native membrane. To study pMMO, we performed several bioinformatics tools to analyze the entire structure of it available in the PDB database. We also carried out molecular docking studies to prove that quinone and duroquinone can bind to several sites of eight pMMO proteins. However, some sites in the orientation are not required by the catalysis process. Furthermore, molecular docking was done for predicting the binding affinity of P450 with target enzymes. Interestingly, our analysis illustrated that pMMO can produce methanol in the presence of quinone and duroquinone and the absence of Cu. Moreover, pmoB1 can interact with P450. Consequently, our findings highlight, for the first time, the significance of studying the membrane of pMMO to provide valuable insights into its functions.

The work contains the results of the analysis of technical literature and author’s research on the use of aluminium slags and products of their processing in metallurgical production. It has been shown that the bulk of reagents derived from secondary aluminum production wastes (APWs) are used with increased sodium and potassium chloride. This creates some inconvenience for out‑of‑furnace steel treatment due to the increased chloride content in the working area. It is proposed for steel processing to use APWs formed during flux‑free melting or dump aluminium slags. This allows to reduce the content of salt fluxes residues to 1.0–1.5 % and to improve working conditions at ladle furnaces when liquefying refining slags.

Density Functional Theory (DFT) and Quantitative Structure-Activity Relationship (QSAR) studies were performed on four benzimidazoles (compounds 1–4) and two benzothiazoles (compounds 5 and 6), previously synthesized by our group. The compounds were also investigated for their binding affinity and interactions with the SARS-CoV-2 Mpro (PDB ID: 6LU7) and the human angiotensin-converting enzyme 2 (ACE2) receptor (PDB ID: 6 M18) using a molecular docking approach. Compounds 1, 2, and 3 were found to bind with equal affinity to both targets. Compound 1 showed the highest predictive docking scores, and was further subjected to molecular dynamics (MD) simulation to explain protein stability, ligand properties, and protein–ligand interactions. All compounds were assessed for their structural, physico-chemical, pharmacokinetic, and toxicological properties. Our results suggest that the investigated compounds are potential new drug leads to target SARS-CoV-2.

The current COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants, remains a serious health hazard globally. The SARS-CoV-2 Mpro and spike proteins, as well as the human ACE2 receptor, have previously been reported as good targets for the development of new drug leads to combat COVID-19. Various ligands, including synthetic and plant-derived small molecules, can interact with the aforementioned proteins. In this study, we investigated the interaction of eight phytochemicals, from selected medicinal plants (Aegle marmelos, Azadirachta indica, and Ocimum sanctum) commonly used in Indian traditional medicine, with SARS-CoV-2 Mpro (PDBID: 6LU7), SARS-CoV-2S spike protein (PDB ID: 6M0J) and the human ACE2 receptor (PDB ID: 6M18). All compounds were subjected to density functional theory (DFT) and frontier molecular orbitals (FMO) analysis to determine their geometry, and key electronic and energetic properties. Upon examining the interactions of the phytochemicals with the human ACE2 receptor and the SARS-CoV-2 Mpro, spike protein targets, two compounds (C-5 and C-8) were identified as the best binding ligands. These were further examined in MD simulation studies to determine the stability of the ligand–protein interactions. QSAR, pharmacokinetic and drug-likeness properties studies revealed that C-5 may be the best candidate to serve as a template for the design and development of new drugs to combat COVID-19.

Diabetes is emerging as an epidemic and is becoming a public health concern worldwide. Diabetic nephropathy is one of the serious complications of diabetes, and about 40% of individuals with diabetes develop diabetic nephropathy. The consistent feature of diabetes and its associated nephropathy is hyperglycemia, and in some cases, hyperamylinemia. Currently, the treatment includes the use of medication for blood pressure control, sugar control, and cholesterol control, and in the later stage requires dialysis and kidney transplantation, making the management of this complication very difficult. Bioactive compounds, herbal medicines, and extracts are extensively used in the treatment and prevention of several diseases, and some are reported to be efficacious in diabetes too. Therefore, in this study, we tried to identify the therapeutic potential of phytochemicals used in in silico docking and molecular dynamic simulation studies using a library of 5284 phytochemicals against the two potential targets of type 2 diabetes-associated nephropathy. We identified two phytochemicals (i.e., gentisic acid and michelalbine) that target human amylin peptide and dipeptidyl peptidase-4, respectively, with good binding affinity. These phytochemicals can be further evaluated using in vitro and in vivo studies for their anti-hyperglycemia and anti-hyperamylinemia effects.

Coronavirus disease (COVID-19) is a highly contagious infection caused by a recently identified coronavirus. The first known case was discovered in December 2019 in Wuhan, China. Since then, the illness has spread globally, resulting in an ongoing epidemic. Here, we would like to address one of the most pressing and outstanding questions which rise about COVID-19 during the year and a half since its discovery: what have we learned from COVID-19?

Background: Circulating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood. Methods: To investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments. Findings: Substantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages. Interpretation: Our results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients. Keywords: Exosome, oncomiR, miR-1246, Ovarian cancer, Cav1, P-gp

Abstract Background Grx6 is a yeast Golgi/endoplasmic reticulum protein involved in iron-sulfur binding that belongs to monothiol glutaredoxin-protein family. Grx6 has been biochemically characterized previously. Grx6 contains a conserved cysteine residue (Cys-136). Depending on the active-site sequences, Grxs can be classified to classic dithiol Grxs with a CXXC motif known as classes II and monothiol Grxs with a CXXS motif known as classes I, and Grx6 belongs to the class I with a CSYS motif. Results Our results showed how the loop between the N-terminal and C-terminal can affect the stability. When Grx6 was incubated with FeSO4·7H2O and (NH4)2Fe(SO4)2·6H2O, a disulfide bond was formed between the cysteine 136 and glutathione, and the concentration of dimer and tetramer was increased. The results presented various levels of stability of Grx6 with mutant and deleted amino acids. We also highlighted the difference between the monomer and dimer forms of the Grx6, in addition to comparison of the Fe-S cluster positions among holo forms of poplar Grx-C1, human Grx2 and Saccharomyces cerevisiae Grx6. Conclusions In this paper, we used a combination of spectroscopic and proteomic techniques to analyse the sequence and to determine the affected mutations and deletions in the stability of Grx6. Our results have increased the knowledge about the differences between monomer and dimer structures in cellular processes and proteins whose roles and functions depend on YCA1 in yeast.

Abstract International Agency for Research on Cancer (IARC) estimated that bladder cancer is the ninth most common cancer in the world, with 430,000 new cases and 165,000 deaths in 2012. Bladder cancer represents the fourth most common cancer in men and ninth most common cancer in women. It is the second most prevalent cancer in men 60 years of age or older in United States. Looking further down, continuing advancements in cancer research could potentially offer more choices for clinician and patient with longer survival and better quality of life. Although, bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies; there are limited studies about application of metformin in the management of bladder cancer. Here, I will shed light on the proposed mechanisms of anti-carcinogenic effects of metformin and cohort of these mechanisms with the novel application of metformin as therapy of bladder cancer.